Analysis of survival and prognostic factors of clear cell adenocarcinoma of the prostate: a case–control study for a rare cancer entity

Clear cell adenocarcinoma of the prostate (CCPC) is a rare entity compared to acinar carcinoma of the prostate (APC). The survival rate and prognostic factors of CCPC are still unclear and deserve further study. We downloaded data on prostate cancer from the Surveillance, Epidemiology, and End Results database for 1975–2019. After inclusion and exclusion criteria, we compared APC and analyzed cancer-specific mortality (CSM) and overall mortality (OM) in CCPC patients and prognostic risk factors using a propensity score matching (PSM) study and multivariate Cox regression. We included 408,004 cases of APC as a control group and 130 cases of CCPC as a case group. Compared with APC patients, the incidence of CCPC was extremely low, and the median age of diagnosis was older (72.00 years vs. 69.00 years, p < 0.01). In addition, more rates were diagnosed at an earlier stage (1975–1998, 93.1% vs. 50.2%, p < 0.001), more unstaged or unknown stage ratios (87.7% vs. 42.7%, p < 0.001), and more surgical treatments (66.2% vs. 47.6%, p < 0.001), but the prognosis of CCPC patients was worse. After PSM, the median survival time of CCPC patients was shorter (57.50 month vs. 88.00 month, p < 0.01), the rate of CSM was higher (41.5% vs. 27.7%, p < 0.05), and the rate of OM was higher (99.2% vs. 90.8%, p < 0.01). In the adjusted model 2 after PSM, the CSM risk of CCPC patients reached HR 1.76 (95%CI 1.13–2.72), which was 76% higher than that of APC patients (p < 0.05). It was further found that surgical treatment might benefit CSM in CCPC patients (HR 0.39, 95%CI 0.18–0.82, p < 0.05) in Univariate analysis, but it was insignificant in further multivariate analysis. This is the first large-scale case–control report on the survival risk and prognostic factors of CCPC patients. We found that the prognosis of CCPC patients was significantly worse than that of APC. Surgery might be an effective treatment that may improve its prognosis. Clear cell adenocarcinoma, prostate, acinar carcinoma, survival rate, rare cancer, propensity score matching, case–control study.


Results
Baseline comparison between the case and control groups. We obtained 423,293 cases of APC and 138 cases of CCPC. After exclusion criteria, 408,004 cases of APC and 130 cases of CCPC were included in this study for analysis. We found that compared with APC patients, the incidence of CCPC is extremely low and rare. In addition, the median age of diagnosis of CCPC patients was older (72.00ys vs. 69.00ys, p < 0.01) ( Table 1) (17 cases were between 46 and 60 years old; the age range was 46 to 89 years old), and more rates were in those diagnosed earlier 93.1% vs. 50.2%, p < 0.001), had a higher proportion of unstaged or unknown stage (87.7% vs. 42.7%, p < 0.001), and more received surgical treatment (66.2% vs. 47.6%, p < 0.001). However, the prognosis of CCPC patients was worse. The median survival time was shorter (57.50mo vs. 123.00mo), among which CPCC patients had a higher ratio of CSM (41.5% vs. 20.0%) (Fig. 1A), and a higher ratio of OM (99.2% vs. 68.1%) (Fig. 1B) (all p < 0.001). There were no significant differences in race, marriage, income, radiation therapy, and systemic therapy between the two groups (all p > 0.05).
Comparison between the two groups of case and control after PSM. After PSM, we obtained 130 patients with APC and 130 patients with CCPC. We found that the two groups of patients were perfectly matched in terms of baseline variables, including age, year, race, marriage, income, home, stage, radiation therapy, surgery, and systemic therapy, and there was no significant difference between the two groups (all p > 0.05) ( Table 2). But the prognosis of CCPC patients was still worse, with shorter median survival (57.50mo vs. 88.00mo, p < 0.01), a higher CSM ratio (41.5% vs. 27.7%, p < 0.05) ( Fig. 2A), and a higher OM ratio (99.2% vs. 90.8%, p < 0.01) (Fig. 2B). CPCC patients had a higher risk of cancer-related death than APC patients. We found that no matter before or after PSM, whether in the non-adjusted model, adjusted model 1, or adjusted model 2, CCPC patients had a higher risk of CSM than APC patients (Table 3) (all p < 0.05), among them, in the adjusted model 2 before PSM, the CSM risk of CCPC patients reached HR 2.06 (95%CI 1.11-3.83), which was 106% higher than that of APC patients (p < 0.05). In the adjusted model 2 after PSM, the CSM risk of CCPC patients reached HR 1.76 (95%CI 1.13-2.72), which was 76% higher than that of APC patients (p < 0.05).
Before PSM, the risk of OM in CCPC patients was also significantly increased in adjusted model 2, reaching HR 1.79 (95%CI 1.23-2.61), which was 79% higher than that in APC patients (p < 0.01). However, after PSM, this increased OM was only observed in the non-adjusted model. In adjusted model 1 and model 2, the increased risk of OM in CCPC patients was insignificant (p > 0.05).  (Table 4), which has a protective effect. However, after adding age and stage, this protective effect also became insignificant in multivariate analysis. No other factors, including age and stage, significantly affected OM and CSM (all p > 0.05). This may be related to the fact that the sample size of CCPC patients is already large enough, but more (93.1% from 1975 to 1998) are diagnosed early, and the proportion of patients with effective staging (16/130, 12.3%) is too small, and thus no more meaningful results could be drawn.

Discussion
To our knowledge, this study is the largest sample size reported to CCPC. In this study of ours, for the first time, we compared the survival risks of CCPC patients, including CSM and OM, with common types of APC, and we found that CCPC patients were older at onset, had a worse prognosis, and shorter survival than were expected to be CSM The risk is significantly higher. Therefore, surgical treatment may be essential to improve the prognosis of CCPC. Clear cell adenocarcinoma (CCA), different from clear cell renal cell carcinoma in the kidney, is a rare malignant tumor of the genitourinary tract; its common site is the bladder or renal pelvis, and the prostate is rarely involved; and its common metastatic sites are the lung 7,11,12 . Regarding gender differences, the proportion of CCA in women is higher than in men 7 . Until 2021, Daniel et al. found that CCA reported 247 cases (PubMed in the English literature), including 203 female and 44 male cases, with a male-to-female ratio of 4.6:1 7 . They reported 15 cases of male CCA patients, 7 cases were found in the prostate or prostatic urethra, and the remaining 5 cases were found in the bladder 7 . CCPC originating from the prostate is also known as renal-type clear cell carcinoma of the prostate 7 , based on its pathological appearance similar to clear cell renal cell carcinoma 13 . It should be noted that since primary CCPC is extremely rare when diagnosing CCPC, it is necessary to pay attention to the metastatic prostatic CCA, urothelial clear cell carcinoma, metastatic clear cell renal cell carcinoma, and other rare entities 7 . There were also reports that CCPC may merge APC 14,15 , which should be noted in pathological diagnosis. Immunohistochemical staining of prostate cancer markers may be helpful for diagnosis 15,16 . www.nature.com/scientificreports/ www.nature.com/scientificreports/   7 . In contrast, the patients we included found that the onset age of these patients was generally older, with a median age of 72 years (n = 130) and an IQR (65-79 years old) ranging from 46 to 89 years old, far older than the median onset age of APC patients (The median age of APC patients was 69 years). This may be related to the significant bias of different sample sources and sample sizes. Our conclusion supports that the median age of onset of CCPC patients is relatively older, but many patients are younger (including 17 cases between 46 and 60 years old).
CCA appears to have a generally poor prognosis. Daniel et al. summarized the literature and found that the 1-year survival rate of CCA patients (n = 135) was 60.4%, 33.3% at 2 years, and 19.4% at 3 years 7 . In addition, 15 patients reported they underwent cystectomy, cystoprostatectomy, radical prostatectomy, combined or not combined with lymph node dissection, and subsequent therapies, such as radiation therapy, chemotherapy, or immunotherapy; however, the prognosis is still poor 7 . The CCPC patients we included also underwent surgery, radiotherapy, or systemic treatment, and we found that the prognosis was worse than that of APC patients. By the end of the follow-up, compared with APC matched in age, stage, and treatment, the median survival time of CCPC patients was shorter (57 months vs. 88 months), and the ratios of CSM and OM were higher. After PSM matching and adjustment (adjusted model 2), CCPC, a rare pathological type of prostate, has a 76% increased risk of CSM compared with APC but no significant increase in the risk of OM death. Using univariate and multivariate analysis, their study found that age and distant metastasis indicate a worse prognosis 7 . Interestingly, we only found that surgical treatment had a protective effect on CSM in univariate analysis, and no significant factors affecting OM were found. This may be related to the characteristics of our sample because the stage of more than 70% of CCPC patients is unknown, and the proportion of radiotherapy and systemic treatment is low. Combined with previous studies, age, stage, and treatment should have a meaningful impact on the survival and prognosis of such patients.
This study had some limitations. As mentioned above, although the sample size of our included CCPC patients was already significant, the vast majority were diagnosed between 1975 and 1998. Most patients lacked effective staging, so more meaningful results could not be obtained. It also made our research conclusions had a particular deviation. In addition, as a retrospective study, we only included part of the data in North America covered by the SEER database, so our conclusions could have been more extensive. Furthermore, the basic health status of these patients, which may contribute to the survival rate, needed to be analyzed but it was not available in the database. Our study found that the surgical treatment was insignificant in multivariate analysis after adding age and stage. No other factors, including age and stage, were supposed to be two potential critical factors that significantly affected OM and CSM in many cancer entities. Still, our study did not identify any significant prognostic risk factors for CCPC beyond surgical treatment as a single variable. In our opinion, potential reasons to interpret these results might be due to a relatively small number of CCPC cases, these cases came from a relatively large period, and even many of them were diagnosed between 1975 and 1998, during which medical care was relatively backward especially the oncological surgical outcomes. Furthermore, some other important parameters that may affect the survival rate of CCPC patients were missing in our study, including tumor size, tumor stage, lymph node involvement, distant metastasis or not, and free surgical margin or not, as they were not well recorded in the current form of the SEER database. However, as in many rare PC studies, our research might still bring specific reference significance to medical care providers and patients.

Conclusions
This is the first time a large sample size has been reported on the survival risk and prognostic factors of CCPC patients. We compared this rare prostate malignancy with APC and found that the prognosis of CCPC patients was significantly worse than that of APC, especially since the risk of CSM was significantly increased. Surgery might be an effective treatment modality that might improve its prognosis. Table 4. Univariate and multivariate analysis of factors affecting the survival rate of CCPC patients. *Extremum. CCPC = Clear cell adenocarcinoma of the prostate; APC = acinar carcinoma of the prostate; CSM = cancer-specific mortality; OM = overall mortality; CI = confidence interval; HR = hazard ratio.